**8. Antibacterial photodynamic therapy folate targeting**

A recent research report has found that folate receptor expression is significantly higher in animal tissues infected with Methicillin-resistant Staphylococcus aureus (MRSA) compared to in uninfected control tissues. The researchers exploited this finding by incorporating vancomycin in folate-decorated liposomes for folate overexpression targeting of the MRSA-infected tissue. They found that the bactericidal and biofilm inhibition effects of the folate-decorated liposomes incorporating vancomycin was higher compared to direct vancomycin application, suggesting superior MRSA targeting and delivery of the drug [90]. The targeting potential of folate functionalization was also confirmed by the superior targeting and antibacterial enhancement of the efficacy of folate-functionalized cerium NPs [91]. This has been widely exploited in PDT studies. Recently, for example, titanium dioxide NPs have been conjugated with folic acid and a phthalocyanine PS for targeted anticancer PDT [92].

The folate over-expression disease cell-targeting mechanism is illustrated in **Figure 10**. It involves the functionalization of the PS-carrier NPs with folic acid. These NPs will bind to the folate receptors followed by enhanced endocytosis by the disease cells because there is enhanced expression of the folate receptors on the disease cells. Once inside the disease cells, the NPs are induced by the disease cell internal microenvironment to release their PS cargo, thus initiating the PDT cell death pathways.

Therefore, in addition to their well-known folate over-expression-enabled cancercell targeting, folate-functionalized NPs incorporating PDT PSs could be used to target bacterial infection for enhanced antibacterial PDT. It is therefore quite surprising that this potential of folate targeting bacterial infection has hardly been investigated as a bacterial targeting strategy in antibacterial PDT. In this regard, the potential of the findings of the folate receptor over-expression of MRSA by Vanamala et al. [90] could be the groundbreaking research that will lead to folate-targeting applications in antibacterial PDT. Therefore, studies are required to determine the microbial infection universality of the higher folate receptor expression found in MRSA-infected tissues compared to in uninfected control tissues.

*Important Advances in Antibacterial Nanoparticle-Mediated Photodynamic Therapy DOI: http://dx.doi.org/10.5772/intechopen.113340*

#### **Figure 10.**

*The folate over-expression disease cell-targeting mechanism.*

### **9. Nanoparticles as agents for photodynamic therapy combination therapies**

Nanotechnology has taken a prime position in PDT combination therapeutics research where NPs, due to their small size and huge volume-to-surface area ratio, can absorb and otherwise load large quantities of PSs and the therapeutic agents required for the PDT combination therapy. In combining PDT with antibacterial chemotherapy, for example, NPs are loaded with antibacterial PDT PSs and antibiotic drugs. In this combination therapy, the NPs can act not only as drug and PS carriers and delivery agents but also as bacterial infection-targeting agents [93]. Nanoconjugates that are either inherently cationic or rendered cationic by virtue of cationic PS capping agents have shown selectivity for bacterial pathogens and bacterial infection. For example, polymeric chlorin-e6-incorporating nanoconjugate systems that become cationic at slightly acidic pH were reported to show pH-dependent bacterial selectivity and efficacy variation [94], while a zeolite-based inorganic NP, capped with the cationic tetravalent silicon phthalocyanine PS, showed a positive zeta potential, selectivity for bacterial infection, and enhanced efficacy [95]. However, the primary purpose of multifunctional nanoconjugate systems is to incorporate functionalities that enable the desired combination therapy into nanoconjugate systems. For example, to enable the combination of antibiotic chemotherapy with PDT, a nanoconjugate system consisting of a core of gold and a shell of silver was passivated with 4-mercaptobenzoic acid. Subsequently, the mercaptobenzoic acid shell of the gold NPs was modified by conjugation with vancomycin and loaded with the phthalocyanine PS to enable vancomycin-mediated antibiotic chemotherapy in combination with phthalocyanine-mediated PDT [96].
